Significant progress has been made in the understanding of embryonic competence and endometrial receptivity since the inception of Assisted Reproductive Technologies (ART). The endometrium is a highly dynamic tissue that plays a crucial role in the establishment and maintenance of normal pregnancy. In response to steroid sex hormones, the endometrium undergoes marked changes during the menstrual cycle that are critical for acceptance of the nascent embryo. There is also a wide body of literature on systemic factors that impact ART outcomes. Patient prognosis is impacted by an array of factors that tip the scales in her favor or against success. Recognizing the local and systemic factors will allow clinicians to better understand and optimize the maternal environment at the time of implantation. This review will address the current literature on endometrial and systemic factors related to impaired implantation and highlight recent advances in this area of reproductive medicine.

Alterations of the human microbiome are a known characteristic of various inflammatory disease states and have been linked to spontaneous preterm birth and other adverse pregnancy outcomes. Recent advances in metagenomic research have proven that the placenta harbors its own rich diverse microbiome, even in clinically healthy pregnancies, and preterm birth may be a result of hematogenous infection rather than exclusively ascending infection as previously hypothesized. In this review, we describe the microbiome in healthy nongravid and gravid women to contrast it with the alterations of the microbiome associated with spontaneous preterm birth. We also discuss the importance of host gene-environment interactions and the potential for microbiota-specific targeted therapies to reduce the risk of adverse pregnancy outcomes.

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder characterized by theca cell hyperplasia and excessive androgen production. An increasing body of evidence has pointed to a close association between PCOS and low-grade chronic systemic inflammation. However, the mechanistic basis for this linkage is unknown. Therefore, we evaluated the effects of the inflammatory agents lipopolysaccharide (LPS) and IL-1β on rat theca-interstitial cells (TICs). We found that incubation with either LPS or IL-1β elicited a dose-dependent increase in both TIC viability and androgen production. Using RNA sequencing analysis, we found that both of these inflammatory agents also triggered profound and widespread shifts in gene expression. Using a stringent statistical cutoff, LPS and IL-1β elicited differential expression of 5201 and 5953 genes, respectively. Among the genes upregulated by both LPS and IL-1β were key regulatory genes involved in the cholesterol and androgen biosynthesis pathways, including Cyp17a1, Cyp11a1, Hsd3b, and Hmgcr. This provides a molecular explanation for the mechanism of action of inflammatory agents leading to increased androgen production. Gene ontology and pathway analysis revealed that both LPS and IL-1β regulated genes highly enriched for many common functions, including the immune response and apoptosis. However, a large number of genes (n = 2222) were also uniquely regulated by LPS and IL-1β, indicating that these inflammatory mediators have substantial differences in their mechanism of action. Together, these findings highlight the potential molecular mechanisms through which chronic low-grade inflammation contributes to the pathogenesis of androgen excess in PCOS.

Recurrent pregnancy loss (RPL) is defined by two or more failed pregnancies and accounts for only 1-5% of pregnancy failures. Treatment options for unexplained RPL (uRPL) are limited. Previous studies suggest a link between delayed implantation and pregnancy loss. Based on this, a timely signal for rescue of the corpus luteum (CL) using human chorionic gonadotrophin (HCG) could improve outcomes in women with uRPL. This retrospective cohort study included 98 subjects with uRPL: 45 underwent 135 monitored cycles without HCG support; and 53 underwent 142 cycles with a single mid-luteal HCG injection. Based on Log-rank Mantel-Cox survival curves, miscarriage rate and time to pregnancy decreased in the HCG group (P = 0.0005). Women receiving luteal HCG support had an increased chance of an ongoing pregnancy compared with those not receiving it (RR = 2.4; 95% CI 1.4-3.6; number need to treat (NNT) = 7; 95% CI 4-18). Subjects receiving HCG support had a significant absolute risk reduction (ARR) of miscarriage (P < 0.001; ARR = 11.5%; 95% CI 3.6-19.5; NNT = 9(5-27). These data suggest restoration of synchrony and CL support improves outcomes in women with RPL. Further randomized controlled trials of luteal-phase HCG in women with RPL appears warranted.